The overall objective of this research is to understand the factors affecting the uptake of macromolecules by the arterial wall, and particularly the mediation of this uptake by local hemodynamics. The interest in macromolecular transport is prompted by its importance in the genesis and development of atherosclerosis. The mediation of arterial uptake by hemodynamic factors is of particular interest because the distribution of atherosclerotic lesions suggests that hemodynamic factors may be involved in the localization of the disease; furthermore, there is evidence that hemodynamic stresses can influence local arterial permeability. A primary hypothesis of this research is that an important fraction of the transendothelial flux occurs during increases in permeability that occur in response to changes in flow; accordingly, particular emphasis is placed on the dynamic response of the barrier function of the vessel wall to changes in the hemodynamic environment. The research objectives are addressed through a unique combination of animal experiments and in vitro flow simulations. In a series of baseline experiments, the spatial variation of albumin, permeability in the terminal aorta and iliac-femoral arteries of normally behaving minipigs will be obtained, using Evans Blue dye as the primary marker. A novel telemetry device will be implanted in the pigs to obtain phasic flow data in these segments. The distribution of wall shear rates in the regions of interest will be obtained from laser Doppler anemometry in compliant flow- through replicas of the vessels, extending from the celiac orifice into the femoral arteries; the telemetry data will be used to prescribe the experimental flow wave. The relation between hemodynamic stress and albumin uptake in these normal animals will be assessed. The techniques employed in the baseline studies will next be used to define the time course of the change in permeability Induced by altered flow. The flow changes will be produced experimentally by stenoses or reversible arteriovenous shunts. The relation between the permeability response (e.g., amplitude, time constants), and the local wall shear and change in shear, will be examined. The effects of hypercholesterolemia on vascular permeability and its dynamic response to changes in flow will be examined as well.